308110-36-3Relevant academic research and scientific papers
Novel compounds
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, (2008/06/13)
Compounds of general formula (I), wherein R1 is selected from phenyl, pyridinyl, thiophenyl, furanyl, imidazolyl; each phenyl ring and heteroaromatic ring optionally and independently being further substituted by 1, 2 or 3 substituents selected
New diarylmethylpiperazines as potent and selective nonpeptidic δ opioid receptor agonists with increased in vitro metabolic stability
Plobeck,Delorme,Wei,Yang,Zhou,Schwarz,Gawell,Gagnon,Pelcman,Schmidt,Yue,Walpole,Brown,Zhou,Labare,Payza,St-Ogne,Kamassah,Morin,Projean,Ducharme,Roberts
, p. 3878 - 3894 (2007/10/03)
Nonpeptide δ opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl(1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human δ receptor (IC50 = 11 nM, μ/δ = 740, κ/δ > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for δ receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for δ binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)-methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, μ/δ = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.
